ISOLATION OF A NOVEL POTASSIUM CHANNEL GENE HSKCA3 CONTAINING A POLYMORPHIC CAG REPEAT - A CANDIDATE FOR SCHIZOPHRENIA AND BIPOLAR DISORDER

Many human hereditary neurodegenerative diseases are caused by expande d CAG repeats, and anonymous CAG expansions have also been described i n schizophrenia and bipolar disorder. We have isolated and sequenced a novel human cDNA encoding a neuronal, small conductance calcium-activ ated potassium channel (hSKCa3) that contains two arrays of CAG trinuc leotide repeats. The second CAG repeat in hSKCa3 is highly polymorphic in control individuals, with alleles ranging in size from 12 to 28 re peats. The overall allele frequency distribution is significantly diff erent in patients with schizophrenia compared to ethnically matched co ntrols (Wilcoxon Rank Sum test, P= 0.024), with CAG repeats longer tha n the modal value being over-represented in patients (Fisher Exact tes t, P= 0.0035). A similar, non-significant, trend is seen for patients with bipolar disorder. These results provide evidence for a possible a ssociation between longer alleles in the hSKCa3 gene and both of these neuropsychiatric diseases, and emphasize the need for more extensive studies of this new gene. Small conductance calcium-activated KI chann els play a critical role in determining the firing pattern of neurons. These polyglutamine repeats may modulate hSKCa3 channel function and neuronal excitability, and thereby increase disease risk when combined with other genetic and environmental effects.